The gastrointestinal tract, (“GI”) particularly the small intestines, is the primary site for the absorption of nutrients and most bioactive agents. To accommodate the amount of absorption that must take place in the small intestines, the surface area is enlarged due to the presence of villi and microvilli. However, before a bioactive compound is transferred from the intestinal lumen to the blood, the compound may have to withstand degradation or deactivation by the various components of the luminal contents. Moreover, the compound may be required to pass through several absorption barriers, such as the mucous layer and the intestinal brush-border membrane. Many compounds pass these barriers easily, but there are many nutrients and bioactive agents to which these barriers represent a serious obstruction.
There are many contributing factors which can affect the oral bioavailability of drugs in the gastrointestinal tract. They include for example, characteristics of the GI tract itself, such as the thickness of the epithelium, the surface area, and blood flow, as well as the local physical and chemical environment. Additionally, absorption may be affected by characteristics of the drug substance itself, such as its solubility in water, its chemical stability and molecular weight.
Cephalosporin is the general term for a group of antibiotic derivatives of cephalosporin C, which is obtained from the fungus Cephalsporium Acremonium. First generation cephalosporins and most second generation cephalosporins are functional in oral dosage forms, though they may be ineffective against many forms of bacteria, such as those found in typical hospital infections. Many third generation cephalosporins, such as ceftiofur, cefixime, cefepime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftizoxime and ceftriaxone, due to their broad spectrum of activity, are effective against some bacterial strains that are resistant to many first and second generation cephalosporins. However, since they are generally not orally bioavailable they must be given by injection. There are several contributing factors to the low absorption in the intestines of third generation cephalosporins after oral administration. First, these antibacterial agents are generally highly ionized and hence are very polar and hydrophillic. These properties do not allow them to readily penetrate the hydrophobic intestinal mucosal membrane. Second, due to their reactive properties, these antibacterial agents are generally unstable in an aqueous environment such as in gastric juices and small intestinal fluids.
Therefore, these cephalosporins have been less effective when administered by other than parenteral routes to treat systemic bacterial infections. Frequently these agents must be given more than once daily to achieve the desired level of efficacy. The necessity of obtaining treatment through intravenous (i.v.) or intramuscular (i.m.) injections is inconvenient, as such treatments often require the services of doctors, nurses, or other trained technicians. Additionally, injections can be painful and cause undue physical and psychological stress to many patients, especially to pediatric patients.
Although ionic surfactants, such as sodium lauryl sulfate, or chelating agents such as EDTA, have been found in some cases to enhance intestinal absorption of large molecules, these substances are known to be harmful to the mucosal membrane.
Other technologies have shown some promise in providing compositions and methods for delivering third generation cephalosporins orally through increased intestinal absorption. In U.S. Pat. No. 4,525,339, β-lactam antibacterial agents were shown to penetrate the mucosal membrane of the intestines by co-administering C2-C12 fatty acid mono-, di-, or triglycerides (i.e. such as Capmuls) as absorption enhancers. In U.S. Pat. No. 5,190,748, absorption of antibacterial agents (such as ceftriaxone) through oral and rectal routes was enhanced by utilizing a two-component absorption enhancing system comprising an ether of a C6-C18 alcohol and a polyoxyethylene glycol together with a second component selected from the group consisting of polyoxyethylene glycol C6 to C18 glyceride esters, C6 to C18 carboxylic acids or salts thereof, and esters of two or more C6 to C18 carboxylic acids, glycerol, and a polyoxyethylene glycol. Additionally, in U.S. Pat. No. 5,318,781, absorption of antibacterial agents (such as ceftriaxone) through oral and rectal routes was enhanced by utilizing a two-component absorption enhancing system comprising Laureth-12 and a second component salt of capric acid and caprylic acids, and a carrier. For optimum absorption, the antimicrobial agent containing the two component enhancer system disclosed therein may include Miglyol-812, which is a capryllic/capric triglyceride. In U.S. Pat. No. 4,722,941, the permucosal absorption of various therapeutics, including antibacterial agents, is reported to be enhanced by the use of fatty acids and saturated or unsaturated fatty acid glycerides.
Other disclosures related to improvements in the intestinal delivery of antibiotics include, for example, oral preparations combining a polymer which is soluble only at pH 5.5 or higher and an insoluble polymer targeted for release in the large intestine (European Patent 49,590); and a solid oral dosage form coated with an appropriate amount of anionic polymer WO 83/00435).
Although each of these systems are somewhat effective in delivering antibacterial agents through the mucosal membrane after oral delivery, each has drawbacks that prevent their widespread use. Some of the compositions and/or methods do not provide significant enough drug delivery such that functional use is practical. Additionally, other compositions and/or methods of mucosal delivery are too costly. As the benefits of third generation cephalosporins and other antibacterial agents have become apparent, it is desirable to provide compositions and methods for administering these antibacterial agents orally, and thus, provide an administration route that is more convenient and cost effective to the patient, and enhances functional concentration of antimicrobial agent that may be absorbed.
Low absorption of oral antimicrobial agents is detrimental for a variety of reasons. Efficacy of the drug may be reduced or eliminated due to the low amounts of drug crossing from the GI tract into the systemic circulation. Safety and tolerability may be compromised since a large amount of the drug ingested may end up in the colon, causing diarrhea, colitis and other gastrointestinal problems. As a result, there may be an increased incidence of drug resistant organisms “selected” in the colon due to the higher levels of drug present.
The present invention addresses the need for orally bioavailable antimicrobial agents by providing compositions and methods for improving the absorption of antimicrobial agents that overcome the difficulties associated with the methods and compositions known in the art.